Hepatitis C virus (HCV) is a member of the family Flaviviridae. It is a virus provided with a viral envelope having a mainly lipid composition and a icosahedral capsid containing a single-stranded RNA molecule about 9,600 nucleotide base long encoding a single polyprotein containing 3,000 amino acids. In the polyprotein, which is processed by viral and cellular proteases, at least 10 distinct viral proteins can be identified which are critical for the replication and assembly of the viral progeny.
According to estimates by the World Health Organization, hepatitis C-infected people in the world are about 200 millions, with an annual increase of about 3 or 4 millions.
The compound (S)-isopropyl-2-(((S)-(((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1 (2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino) propanoate, known as Sofosbuvir, is a prodrug used to treat hepatitis C. Its main metabolite, 2′-deoxy-2′-α-fluoro-β-C-methyluridine-5′-monophosphate, inhibits RNA polymerase that the hepatitis C virus uses to replicate its RNA. This compound has the following structural formula:

Sofosbuvir and other similar compounds were first described in the international patent application WO 20081121634 A2. This application describes a process comprising a phosphorylation of nucleoside (B) with phosphorus chloride (A) in the presence of N-methylimidazole followed by preparative chromatographic purification to give Sofosbuvir as a mixture of phosphorus diastereoisomers, according to the following scheme:

Said mixture is then purified by chromatography on chiral stationary phase to give Sofosbuvir in a diastereomerically purified form.
Two different chromatography separations make this process non-industrializable. An ameliorative process for the preparation of Sofosbuvir is described in the international application WO 2010/135569 A1. This patent application describes two possible routes for the preparation of the diastereomerically purified form of Sofosbuvir. The first involves the phosphorylation of nucleoside (B) with phosphochloride (A) in the presence of N-methylimidazole to give a mixture of products (C), (D) and (E). This mixture is treated with tert-butyldimethylsilyl chloride in order to selectively protect the hydroxyl in position 5′ of compound (E) and purified by chromatography to give Sofosbuvir diastereomericaliy mixed with the phosphorous, which is finally converted into the diastereomerically purified form by crystallization:

Drawbacks of this route derive from the poor selectivity of the phosphorylation reaction and from the need to derivatize the reaction mixture with tert-butyidimethylsilyl chloride to make (inter alia by chromatography, a poorly industrializable technique) the compound of interest cleavable.
The second approach involves the conversion of (A) into the diastereoisomeric mixture of phosphoramidates (L). The desired diastereomer (H) is isolated by fractional crystallization and then condensed with a protected nucleoside (F) to give a protected form of Sofosbuvir (G) which is converted into the latter by treatment with sodium sulfite and sodium metabisulfite.

A further method for the preparation of Sofosbuvir in the form of diastereomeric mixture is described in Tetrahedron (2011), 67, 5487-5493 and involves the treatment of a protected nucleoside (I) with phosphochloride (A) in the presence of N-methylimidazole and subsequent hydrogenolysis of the protecting group in position 3′:

However, the process described leads to the formation of a mixture of about 35:65 diastereoisomers in which (Sp)-Sofosbuvir (the compound of interest) is the minority component and from which the isolation of the latter by crystallization is not actually feasible.
Finally, the international application WO 2014/076490 A1 describes the preparation of an enriched mixture of the two phosphorus diastereoisomers of Sofosbuvir by treating phosphochioride (A) with a nucleoside (M) in the presence of a metal salt selected from copper, iron, lanthanum and ytterbium.

Although potentially advantageous, this procedure is affected by very poor conversions (20% as mentioned in example 47).
The object of the present invention is to provide a method for the synthesis of Sofosbuvir, which is carried out with high yields, in a small number of synthesis steps and which provides the desired products with suitable purity for pharmaceutical use.